OKRIDO 6 MG / ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Okrido

6 mg/ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient of Okrido is prednisolone as the sodium phosphate ester. 1 ml oral solution contains 6 mg prednisolone (as sodium phosphate).

Excipients with known effect: Okrido contains Sorbitol and sodium.

For full list of excipients, see section 6.1

Oral solution

Okrido is a colourless, transparent, homogeneous and syrupy solution in a brown glass bottle with a child-proof white screw cap.

4.1 Therapeutic indications

Okrido is indicated for the treatment of diseases which require a systemic therapy with glucocorticoids. This is dependent on clinical presentation and severity:

Allergy and anaphylaxis: Severe allergic and anaphylactic reactions, bronchial asthma.

Arteritis/colla­genosis: Giant cell arteritis, mixed connective tissue disease, polyarteritis nodosa.

Blood disorders: Haemolytic anaemia (autoimmune), leukaemia (acute and lymphatic), malignant lymphoma, multiple myeloma, idiopathic thrombocytopenic purpura, polymyositis.

Cardiovascular disorders: Rheumatic fever with severe carditis.

Substitution therapy: Adrenal cortex insufficiency of any pathogenesis (e.g.

M. Addison, congenital adrenal hyperplasia, adrenalectomy, ACTH

deficiency) after the growing phase (first-choice therapies are hydrocortisone and cortisone)

Gastrointestinal disorders: Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis.

Infectiology: Toxic conditions in the context of severe infectious diseases (in connection with antibiotics/ chemotherapy), e.g. tuberculous meningitis, severe form of progressive pulmonary tuberculosis.

Neurology: Myasthenia gravis (first-choice therapy is azathioprine), chronic Guillain-Barre syndrome, Tolosa-Hunt syndrome, polyneuropathy with monoclonal gammopathy, subacute demyelating polyneuropathy, multiple sclerosis (for gradual oral reduction after high-dose parenteral glucocorticoid administration), acute exacerbations of multiple sclerosis, cerebral oedema as a result of cerebral metastases.

Ocular diseases: In systemic diseases involving the eyes and in

immunological processes in the orbita and in the eye: optic neuropathy (e.g. giant cell arteritis, anterior ischaemic optic neuropathy (AION), traumatic optic neuropathy), Behget's disease, sarcoidosis

Renal disorders: Selected cases of nephrotic syndrome

Pneumology: Asthma (administration of bronchodilators at the same time is

recommended), acute COPD exacerbation (recommended duration of therapy is up to 10 days), interstitial lung diseases such as acute alveolitis, pulmonary fibrosis , long-term therapy of chronic forms of sarcoidosis stages II and III (with respiratory distress, cough and worsening of pulmonary function values), prophylaxis of infant respiratory distress in premature babies

Diseases of the upper airways: Severe forms of pollinosis and allergic rhinitis, after failure of intra-nasally administered glucocorticoids, acute laryngeal and tracheal stenoses: Quincke oedema, obstructive subglottic laryngitis (croup)

Rheumatic disorders: Rheumatoid arthritis, polymyalgic rheumatica, juvenile chronic arthritis, systemic lupus erythematosus, dermatomyositis, polymyositis.

Skin disorders: Pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, pyoderma gangrenosum.

Miscellaneous: Hyperpyrexia, as an immunosuppressant in organ transplantations, as an adjuvant in the prevention of nausea and vomiting in connection with cancer therapy with oncolytics with a severe emetogenic effect, multiple organ failures

4.2 Posology and method of administrationPosology

The initial dosage of prednisolone may vary from 5–100 mg daily depending on the disorder being treated. Preferably taken as a single dose in the morning, after breakfast. Divided daily dosage may be employed if required.

The following therapeutic guidelines should be kept in mind for all therapy with corticosteroids:

Corticosteroids are palliative symptomatic treatment by virtue of their antiinflammatory effects; they are never curative.

The appropriate individual dose must be determined by trial and error and must be reevaluated regularly according to activity of the disease.

As corticosteroid therapy becomes prolonged, and as the dose is increased, the incidence of disabling side-effects increases.

Abrupt cessation of prolonged high dosage corticosteroid therapy is associated with a significant risk of potentially life-threatening adrenal insufficiency. (See section 4.4 Special warnings and precautions for use).

In general, initial dosage should be maintained or adjusted until the anticipated response is observed. The dose should then be gradually reduced until the lowest dose which will maintain an adequate clinical response is reached.

During prolonged therapy, dosage may need to be temporarily increased during periods of stress or during exacerbations of the disease.

When the drug is to be stopped, it must be withdrawn gradually and not abruptly.

If there is a lack of clinical response to prednisolone, the drug should be gradually discontinued and the patient transferred to alternative therapy.

Intermittent dosage regimen: A single dose of prednisolone on alternate days or at longer intervals is acceptable therapy for some patients. When this regimen is practical, the degree of pituitary-adrenal suppression can be minimised.

Specific dosage guidelines: The following recommendations for some corticosteroi­dresponsive disorders are for guidance only. Acute or severe disease may require initial high dose therapy with reduction to the lowest effective maintenance dose as soon as possible. Dosage reductions should not exceed 5–7.5mg daily during chronic treatment.

Allergic and skin disorders: Initial doses of 5–15mg daily are commonly adequate.

Collagenosis: Initial doses of 20–30mg daily are frequently effective. Those with more severe symptoms may require higher doses.

Rheumatoid arthritis: The usual initial dose is 10–15mg daily. The lowest daily maintenance dose compatible with tolerable symptomatic relief is recommended.

Blood disorders and lymphoma: An initial daily dose of 15–60mg is often necessary with reduction after an adequate clinical or haematological response. Higher doses may be necessary to induce remission in acute leukaemia.

Although appropriate fractions of the adult dose may be used, dosage will usually be determined by clinical response as in adults.

Children: Aged 1–6 years- One quarter the adult dose.

Aged 7–11 years- One half the adult dose.

Aged 12–17 years- Three quarters the adult dose.

Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo-pituitary adrenal axis and growth retardation, treatment should be administered where possible as a single dose on alternate days.

Elderly: Treatment of elderly patients, especially if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age, particularly diabetes, hypertension, hypokalaemia, osteoporosis, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

For oral use

Okrido is best taken undiluted.

Shake well before use.

4.3 Contraindications

Systemic infections, unless specific anti-infective therapy is employed.

– Hypersensitivity to prednisolone or to any of the excipients listed in section 6.1. – Gastric ulcer and duodenal ulcer

– Acute infections, in particular virus infections and systemic fungal infections

– Tropical worm infections

– Administration after live virus immunization

– Herpes simplex oculi

4.4 Special warnings and precautions for use

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5 mg prednisolone or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5mg prednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40 mg daily of prednisolone, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks

When a short course has been prescribed within one year of cessation of long-term therapy (months or years),

Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy,

Patients receiving doses of systemic corticosteroid greater than 40mg daily of prednisolone (or equivalent),

Patients repeatedly taking doses in the evening.

Patients should carry ‚Steroid treatment‘ cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Suppression of the HPA axis and other undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity. (See dosage section).

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. If the patient is a child parents must be given the above advice. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Patients should be advised to take particular care to avoid exposure to measles and to seek immediate advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Live vaccines should not be given to individuals with impaired immune responsiveness caused by high doses of corticosteroids. The antibody response to other vaccines may be diminished.

Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or hypertension or congestive heart failure.

Corticosteroids may worsen diabetes mellitus, osteoporosis, hypertension, glaucoma and epilepsy and therefore patients with these conditions or a family history of them should be monitored frequently.

Care is required and frequent patient monitoring necessary where there is a history of severe affective disorders (especially a previous history of steroid psychosis), previous steroid myopathy, peptic ulceration, hypothyroidism, recent myocardial infarction or patients with a history of tuberculosis.

In patients with liver failure, blood levels of corticosteroid may be increased, as with other drugs which are metabolised in the liver. Frequent patient monitoring is therefore necessary.

Physicians should be aware that corticoids have been reported to precipitate porphyria. As well, one case of a reversible Steven-Johnson-Syndrome (SJS) was reported in connection with prednisolone treatment.

Scleroderma renal crisis

Caution is required in patients with systemic sclerosis because of an increased incidence of (possibly fatal) scleroderma renal crisis with hypertension and decreased urinary output observed with a daily dose of 15 mg or more prednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicinal product contains 1.2 mmol sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

Use in Children: Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible.

Use in the Elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypopotassaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, ephedrine and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

Mifepristone may reduce the effect of corticosteroids for 3–4 days.

Erythromycin and ketoconazole may inhibit the metabolism of some corticosteroids.

Ciclosporin increases plasma concentration of prednisolone. The same effect is possible with ritonavir.

Oestrogens and other oral contraceptives may potentiate the effects of glucocorticoids and dosage adjustments may be required if oral contraceptives are added to or withdrawn from a stable dosage regimen.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.

The growth promoting effect of somatropin may be inhibited by the concomitant use of corticosteroids.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.

The efficacy of coumarin anticoagulants and warfarin may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Concomitant use of aspirin and Non Steroidal Anti-Inflammatory Drugs (NSAIDs) with corticosteroids increases the risk of gastro-intestinal bleeding and ulceration.

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

The hypopotassaemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone, are enhanced by corticosteroids. The risk of hypopotassaemia is increased with theophylline and amphotericin. Corticosteroids should not be given concomitantly with amphotericin, unless required to control reactions.

The risk of hypopotassaemia also increases if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline. The toxicity of cardiac glycosides is increased if hypopotassaemia occurs with corticosteroids.

Concomitant use with methotrexate may increase the risk of haematological toxicity.

High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also warnings).

In rare cases the concomitant treatment with corticosteroids and fluoroquinolones may increase the risk of tendon rupture.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6 Fertility, pregnancy and lactationFertility

Animal studies do not indicate reproductive toxicity (see section 5.3)

The ability of corticosteroids to cross placenta varies between individual drugs, however, 88% of prednisolone is inactivated as it crosses the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation.

Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Patients with pre-eclampsia or fluid retention require close monitoring.

Depression of hormone levels has been described in pregnancy but the significance of this finding is not clear.

Corticosteroids are excreted in small amounts in breast milk. However doses of up to 40 mg daily of prednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast-feeding are likely to outweigh any theoretical risk.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitaryadrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment. (See other special warnings and precautions)

Endocrine/meta­bolic:

Suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy. Negative protein and calcium balance. Increased appetite.

Corticoids in general may precipitate porphyria.

Anti-inflammatory and Immunosuppressive effects:

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (See other special warnings and precautions).

Musculoskeletal:

Osteoporosis, vertebral and long bone fractures, avascular osteonecrosis particularly of the femoral head may occur after prolonged corticosteroid therapy or after repeat short courses involving high doses, tendon rupture. Proximal myopathy.

Fluid and electrolyte disturbance:

Sodium and water retention, hypertension, potassium loss, hypopotassaemic alkalosis.

Neuropsychiatric:

Euphoria, psychological dependence, depression, insomnia and aggravation of schizophrenia. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Aggravation of epilepsy.

Ophthalmic:

Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Gastrointestinal:

Dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis,nausea.

Dermatological:

Impaired healing, skin atrophy, bruising, telangiectasia, striae, acne.

One case of a reversible prednisolone induced Steven-Johnson-Syndrome (SJS) was reported.

Cardiovascular:

Myocardial rupture following recent myocardial infarction.

General:

Malaise, hiccups, leucocytosis, thromboembolism.

Hypersensitivity including anaphylaxis has been reported.

Withdrawal symptoms and signs:

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. (See other special warnings and precautions)

A ‚withdrawal syndrome‘ may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Corticoids in general may precipitate porphyria.

One case of a reversible prednisolone induced Steven-Johnson-Syndrome (SJS) was reported.

Frequency ‘unknown’:

– Scleroderma renal crisis*

– Vision, blurred (see also section 4.4)

*Scleroderma renal crisis

Amongst the different subpopulations the occurrence of scleroderma renal crisis varies. The highest risk has been reported in patients with diffuse systemic sclerosis. The lowest risk has been reported in patients with limited systemic sclerosis (2%) and juvenile onset systemic sclerosis (1%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Treatment is unlikely to be needed in cases of acute overdosage.

5.

5.1. Pharmacodynamic properties

Corticosteroids for systemic use

ATC code: H02AB06

Okrido contains the equivalent of 6 mg/ml of prednisolone in the form of the 21-disodium phosphate ester. Prednisolone sodium phosphate is a synthetic glucocorticoid with the same general properties as prednisolone itself and other compounds classified as corticosteroids. Prednisolone is four times as active as hydrocortisone on a weight for weight basis.

Prednisolone sodium phosphate is very soluble in water, and is therefore less likely to cause local gastric irritation than prednisolone alcohol, which is only slightly soluble. This is important when high dosages are required, as in immuno-suppressive therapy.

5.2 Pharmacokinetic properties

Absorption

Prednisolone is readily absorbed from the gastrointestinal tract with peak plasma concentrations achieved by 1–2 hours after an oral dose. Plasma prednisolone is mainly protein bound (70–90%), with binding to albumin and corticosteroid-binding globulin. The plasma half-life of prednisolone, after a single dose, is between 2.5–3.5 hours.

Distribution

The volume of distribution and clearance of total and unbound prednisolone are concentration dependent, and this has been attributed to saturable protein binding over the therapeutic plasma concentration ran­ge.

Metabolism

Prednisolone is extensively metabolised, mainly in the liver, but the metabolic pathways are not clearly defined.

Excretion

Over 90% of the prednisolone dose is excreted in the urine, with 7–30% as free prednisolone, and the remainder being recovered as a variety of metabolites.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitol, liquid (non-crystallising), E 420

Glycerol (85 per cent)

Acesulfame potassium

Disodium edetate

Sodium dihydrogen phosphate dihydrate

Sodium hydroxide

Water, purified

Cherry flavour

6.2 Incompatibilities

None known.

6.3 Shelf life

30 months,

6.4 Special precautions for storage

Do not store above 25 °C.

Store in the original package.

Do not refrigerate.

One bottle Okrido is intended for single use only.

6.5 Nature and contents of container

10 or 20 ml brown glass bottle with a child-proof, white polypropylene screw cap and a natural coloured polyethylene adapter insert for a metering syringe. The bottle is enclosed in a carton containing a metering syringe made of polypropylene and silicone (oral syringe, CE0086) with 0.5 to 5.0 ml scale.

natural coloured, 5 ml volume

Barrel

Plunger Seal Piston Inscription

Polypropylene

Polypropylene, Colourant

Silicone

Silicone

Ink

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Pharmapol Arzneimittelver­trieb-GmbH

Kaddenbusch 11

25578 Dageling

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL21587/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

19/04/2010